KR20220154791A - Co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid - Google Patents

Abstract

The present invention relates to a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid, a process for obtaining the co-crystal, and the co-crystal. Combination products and pharmaceutical compositions comprising crystals, and their medical use, in particular for the treatment or prevention of diseases known to be ameliorated by A ₁ adenosine receptor antagonism.

Description

Co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid

The present invention relates to a novel co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid, which is an adenosine A ₁ adenosine receptor antagonist. will be. The co-crystal is useful for the treatment or prevention of diseases known to be ameliorated by antagonism of the A ₁ adenosine receptor.

Adenosine A1 receptor antagonists are used for the treatment or treatment of a variety of diseases including hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases such as multiple sclerosis. useful for prevention (Hocher, B, Adenosine A1 receptor antagonists in clinical research and development , Kidney International (2010) 78, 438-445; Haskσ, G et al, Adenosine receptors: therapeutic aspects for inflammatory and immune diseases , Nature Reviews, volume 7, September 2008, 759).

Specifically, patent application WO 2009/044250 A1 discloses 5-cyano-1,3-thiazole derivatives that are potent A ₁ adenosine receptor antagonists and useful for the treatment of the above-mentioned diseases. In this patent application, 3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid, in particular the (1R,3S) stereoisomer, is disclosed, the structure of which is It is shown below:

Co-crystals of 5-cyano-1,3-thiazole derivatives are not mentioned in the cited document or in any other document known to the applicant.

Although (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid exhibited suitable pharmacological activity, the physical and/or It appears that there is room for improvement of the pharmacological properties, especially its hygroscopicity and bioavailability. Improvement of these properties will aid further pharmaceutical development into drugs.

Thus, a method for improving the hygroscopicity and/or bioavailability of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid would be provided. There is a need.

Thus, the solubility of said (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid with improved hygroscopicity and/or bioavailability and The rate of development of a stable pharmaceutically acceptable form is highly desirable. The present invention addresses these concerns.

Co-crystals are distinguished from salts because, unlike salts, components coexisting in the co-crystal lattice with a defined stoichiometry interact non-ionically. In general, active pharmaceutical ingredients (APIs) and their co-crystal forming compounds (coforms) are considered less than substantial proton transfer if ΔpKa (ΔpKa= pKa(conjugate acid of base) - pKa(acid)) < 1 do. If this criterion is met, the API-coformer entity should be classified as a co-crystal. (Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, February 2018, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm) .

Several properties can be altered by co-crystal formation, such as storage stability, solubility, rate of dissolution, hygroscopicity and bioavailability, etc. considered as one of the first physicochemical properties to be considered. (Izutsu, K et al, Characterization and Quality Control of Pharmaceutical Cocrystals , Chem. Pharm. Bull. 64, 1421-1430 (2016)).

Due to the availability of a large number of pharmaceutically acceptable co-formers and the lack of correlation between the properties of the pharmaceutically acceptable co-formers and the final properties of the co-crystals, finding suitable co-crystals is a difficult process and consequently cannot be predicted a priori.

(1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane co-crystals improving the physicochemical and pharmaceutical properties of carboxylic acid; In particular, hygroscopicity is improved without adversely affecting other important parameters such as crystallinity or bioavailability of the active compound. In particular, (1R,3S)- (1R,3S)- There is a need to reduce the hygroscopicity of 3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) cyclopentane carboxylic acid.

The present invention provides a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid.

Attempts to obtain a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid with a number of potential crystal forming compounds have been attempted. Later, the inventors surprisingly found that gentisic acid, urea and nicotinamide exhibit particularly good properties of hygroscopicity and bioavailability and higher melting points for the compounds in free acid form. Improvements in the above-mentioned properties imply advantages for the production, handling and storage processes of the compounds and for the pharmaceutical properties of the products. Specifically, significant improvements in oral bioavailability have been shown with the co-crystals of the present invention, which will allow administration of significantly lower doses of the compound to achieve target therapeutic levels.

With respect to the subject matter of the present invention, no disclosure is known to the state of the art regarding the preparation and use of any co-crystal of a compound belonging to the family of compounds disclosed in patent application WO 2009/044250 A1, (1R,3S) Co-crystals of -3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and much less co-crystals with gentisic acid, urea and nicotinamide.

Thus, in a first aspect, the present invention relates to (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid, urea and a co-crystal forming compound selected from the group consisting of nicotinamide.

In a second aspect, the present invention relates to a process for the preparation of a co-crystal as defined in the first aspect, comprising:

a) selected from the group consisting of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid, urea and nicotinamide contacting the co-crystal forming compound in the presence of a liquid; and

b) isolating the resulting co-crystal.

In a third aspect, the present invention comprises the co-crystal according to the first aspect and one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme inhibitors (ACE-inhibitors), angiotensin receptor antagonists, statins, beta-blockers, calcium antagonists and diuretics It relates to a combination product that

In a fourth aspect, the present invention relates to a pharmaceutical composition comprising the co-crystal according to the first aspect or the combination product according to the third aspect and a pharmaceutically acceptable excipient.

In a fifth aspect, the present invention relates to a co-crystal according to the first aspect, a combination product according to the third aspect or a pharmaceutical composition according to the fourth aspect, for use as a medicament.

In a sixth aspect, the present invention provides a co-crystal according to the first aspect, a combination product or agent according to the third aspect, for use in the treatment and/or prevention of diseases known to be ameliorated by A ₁ adenosine receptor antagonism. It relates to the pharmaceutical composition according to the 4th aspect.

1 demonstrates the ¹ H NMR spectrum of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid.
2 demonstrates the XRPD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid.
Figure 3 shows (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl, an endothermic event starting at 179.59 °C, which corresponds to the melting point of this compound. ) Demonstrate the DSC pattern of cyclopentane carboxylic acid.
4 is a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid from Example ² ; H-NMR spectrum is demonstrated.
5 is an XRPD of co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid from Example 2; Validate the pattern.
6 is (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazole-2- of Example 2 showing an endothermic event initiated at 181.69° C., which corresponds to the melting point of this co-crystal. The DSC pattern of the co-crystal of ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid is demonstrated.
7 is a 1H- co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2 ^- ylcarbamoyl)cyclopentane carboxylic acid and urea from Example 3. The NMR spectrum is verified.
8 is an XRPD pattern of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea in Example 3; substantiate
9 shows (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazole-2- of Example 3 showing an endothermic event initiated at 197.7° C., which corresponds to the melting point of this co-crystal. The DSC pattern of a co-crystal of monocarbamoyl)cyclopentane carboxylic acid and urea is demonstrated.
10 is ^a 1H co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide from Example 4. - Demonstrate the NMR spectrum.
11 is an XRPD pattern of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide from Example 4. to substantiate
Figure 12 is (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazole-2- of Example 4 showing an endothermic event initiated at 189.55 °C, which corresponds to the melting point of this co-crystal. The DSC pattern of a co-crystal of monocarbamoyl)cyclopentane carboxylic acid and nicotinamide is demonstrated.
13 is a DVS of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid from Example 2. The pattern is demonstrated, which shows the change in weight (%) of the co-crystal as a function of relative humidity (RH).
14 is a DVS pattern of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea in Example 3. Demonstrated, it shows the change in weight (%) of the co-crystal as a function of relative humidity (RH).
15 is a DVS pattern of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide in Example 4. , which shows the change in weight (%) of the co-crystal as a function of relative humidity (RH).
16 shows (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and different co-crystals obtained from Examples 2, 3 and 4. shows a comparison between the DVS patterns of

This patent application discloses several co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid. The following co-crystals are from the group consisting of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid, urea and nicotinamide. It was obtained from a co-crystal forming compound selected from All of them showed improved physicochemical and pharmacokinetic properties with respect to the free acid.

Gentisic acid co-crystal

The inventors have surprisingly found that co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid exhibit the following advantageous properties: It was found to have:

1) Stability in forced conditions (1 week) and 4-week stability analysis: No change in crystallinity, color or any other change in aspect was observed in the obtained co-crystals.

2) Hygroscopicity: Hygroscopicity is lower than that of the free acid, especially under normal storage conditions of drugs (<75% RH).

3) Bioavailability: The improvement of gentisic acid co-crystal in oral exposure and bioavailability compared to free acid was surprising.

Thus, the gentisic acid co-crystals offer advantages in the manufacture of solid dosage forms containing pharmacologically active compounds, which facilitate handling and allow for better dosing regimens. In addition, the gentisic acid co-crystal of the present invention is a stable solid even under forced stability conditions. This co-crystal is particularly superior to the free acid, as can be seen in the example when comparing the change in moisture content achieved by the gentisic acid co-crystal (0.10% at 75% RH) and the free acid (0.43% at 75% RH). Low hygroscopicity up to 75% RH.

Urea co-crystal

A co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea has also been prepared and is shown to have all of the following advantages: Turns out:

1) Stability in forced conditions (1 week) and 4-week stability analysis: No change in crystallinity, color or any other change in aspect was observed in the obtained co-crystals.

2) Hygroscopicity: Hygroscopicity is lower than that of the free acid, especially under normal storage conditions of drugs (<75% RH).

3) Bioavailability: The improvement of urea co-crystal in oral exposure and bioavailability compared to free acid was surprising.

Thus, the urea co-crystals offer advantages in the manufacture of solid dosage forms containing pharmacologically active compounds, which facilitate handling and allow for better dosing regimens. In addition, the urea co-crystal of the present invention is a stable solid even under forced stability conditions. This co-crystal is especially 75% higher than the free acid, as can be seen in the example when comparing the change in moisture content achieved by the urea co-crystal (0.08% at 75% RH) and the free acid (0.43% at 75% RH). Low hygroscopicity up to RH.

nicotinamide co-crystal

The inventors have surprisingly found that a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide has the following advantages: found that:

1) Stability in forced conditions (1 week) and 4-week stability assays: No change in crystallinity, color or any other change in aspect was observed in the co-crystals obtained during both stability assays.

2) Hygroscopicity: It is less hygroscopic than the free acid, especially in the range of 5 to 70% RH.

3) Bioavailability: The improvement of nicotinamide co-crystal in oral exposure and bioavailability compared to the free acid was surprising.

Thus, the nicotinamide co-crystals offer advantages in the manufacture of solid dosage forms containing pharmacologically active compounds, which facilitate handling and permit better dosing regimens. In addition, the nicotinamide co-crystal of the present invention is a stable solid even under forced stability conditions. This co-crystal is less hygroscopic than the free acid, especially in the range of 5 to 70% RH, as can be seen in the example when comparing the change in water content reached by the nicotinamide co-crystal.

As shown in Examples 5 to 8, the obtained co-crystals show improved melting point, hygroscopicity and bioavailability properties relative to the free acid.

Accordingly, a first aspect of the present invention is a mixture of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid with gentisic acid, urea and It relates to a co-crystal with a co-crystal forming compound selected from the group consisting of nicotinamide.

In the context of this invention the term "co-crystal" is used to designate a crystalline material composed of two or more different molecules in defined stoichiometric proportions within the same crystal lattice that interact through nonionic and noncovalent bonds. In general, the co-crystal comprises an API moiety such as (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and a co-crystal forming compound (co-form co-crystal forming agent, guest molecule).

The term "cocrystal forming compound" or "coformer" in the context of this invention is used to designate a component that is typically solid at room temperature and that interacts nonionically with the API in the crystal lattice.

에서 액체인 임의의 물질이며, 바람직하게는 ICH 가이드라인 Q3C(R6)에 따른 클래스 1, 클래스 2 또는 클래스 3 용매는 바람직하게는 물, 메탄올, 에탄올, 이소프로판올, 프로판올, 부탄올, 아세토니트릴, 에틸 아세테이트, i-부틸 아세테이트, 프로판-2-온 (아세톤), 메틸-이소부틸-케톤 (MIBK), 테트라하이드로푸란 (THF), 1,4-디옥산, 디클로로메탄 (DCM), p-자일렌, 에틸 에테르, 메틸 tert-부틸 에테르 (TMBE) 및 헵탄으로 이루어진 군으로부터 선택된다. A liquid in the context of the present invention is room temperature, for example 25

Any substance that is a liquid in , preferably a Class 1, Class 2 or Class 3 solvent according to ICH Guideline Q3C(R6) is preferably water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate , i-butyl acetate, propan-2-one (acetone), methyl-isobutyl-ketone (MIBK), tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), p-xylene, It is selected from the group consisting of ethyl ether, methyl tert-butyl ether (TMBE) and heptane.

In a preferred embodiment, the co-crystal is of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid. .

In a more preferred embodiment, the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to gentisic acid in the co-crystal is is comprised between 0.9 and 1.1, preferably 1:1.

In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid has a weight of about 181.69 A differential scanning calorimetry (DSC) thermogram containing an endothermic peak at °C.

In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid has a ratio of 6.99, characterized by exhibiting an X-ray powder diffraction pattern comprising 2θ° peaks at 13.29, 13.42, 14.02, 17.82 (all of which ± 0.20) 2θ°, wherein the X-ray diffraction pattern is measured using CuKα radiation . In a more preferred embodiment, the X-ray diffraction pattern is 6.99, 13.29, 13.42, 14.02, 17.82, 18.,71, 21.09, 26.34, 26.58, 27.28, 28.24, 31.56 (all of them ± 0.20) 2θ° to 2θ° contains peaks.

In another preferred embodiment, the co-crystal is of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea. .

In a more preferred embodiment, the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to urea in the co-crystal is 0.9 to 1.1, preferably 1:1.

In a more preferred embodiment, a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea is formed at about 197.7°C. Have a differential scanning calorimetry (DSC) thermogram containing the endothermic peak.

In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea has 8.32, 8.82, characterized by exhibiting an X-ray powder diffraction pattern comprising 2θ° peaks at 13.86, 15.60, 16.47, 24.86 (all of them ± 0.20) 2θ°, wherein the X-ray diffraction pattern is measured using CuKα radiation . In a more preferred embodiment, the X-ray diffraction pattern is 7.77, 8.32, 8.82, 13.86, 15.60, 16.47, 18.23, 18.94, 19.38, 19.86, 20.05, 20.71, 21.38, 21.84, 22.76, 23.72, 826.10, 826.02, 24.84. 28.40 (of which all ± 0.20) includes the 2θ° peak at 2θ°.

In a preferred embodiment, the co-crystal is of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide.

In a more preferred embodiment, the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to nicotinamide in the co-crystal is 0.9 to 1.1, preferably 1:1.

In a more preferred embodiment, a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide has a temperature of about 189.55°C. It has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at .

In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide is 6.40, 8.54 , 11.75, 17.29, 20.88, 23.66 (all of which ± 0.20) 2θ° to 2θ° peaks, wherein the X-ray diffraction pattern is measured using CuKα radiation. do. In a more preferred embodiment, the X-ray diffraction pattern is 6.40, 8.54, 11.28, 11.75, 13.02, 17.29, 18.33, 19.56, 20.11, 20.55, 20.88, 21.36, 21.62, 22.73, 22.96, 2,2.56, 2,2.56, 24.61, 24.66, 24.66, 24.66 26.17, 26.46, 27.53, 28.81, 29.36, 30.28, and 32.96 (all of which ± 0.20) contain the 2θ° to 2θ° peaks.

In the present invention, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid has a pKa of 4.3. The ΔpKa between the free acid and the selected co-crystal forming compound is <1 as shown in Table 1 below.

(1R,3S )-3-(5- Cyano -4-phenyl-1,3-thiazole-2- Il carbamoyl ) cyclopentane carboxylic acid Common manufacturing process for co-crystals

In another aspect, the present invention provides a (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclo A process for the preparation of pentane carboxylic acid co-crystals:

a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and a crystal forming compound in the presence of a liquid; and

b) Isolating the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid-coformer cocrystal.

Step a) is a crystal selected from (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) cyclopentane carboxylic acid and gentisic acid, urea and nicotinamide It involves contacting the forming compound in the presence of a liquid. In one embodiment, contacting the two starting compounds can be achieved by mixing them. In one embodiment, the mixture resulting from step a) may be seeded with small crystals of the desired co-crystal compound to promote precipitation, although this is not necessary to obtain the co-crystal.

(1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) cyclopentane carboxylic acid is disclosed in patent application WO 2009/044250A1, incorporated herein by reference. Manufactured using the process

In certain embodiments, when the co-crystal forming compound is gentisic acid, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) in step a) Cyclopentane carboxylic acid and gentisic acid are in a molar ratio of 0:9 to 1:1.5, preferably 1:1 to 1:1.5, preferably 1:1 to 1:1.2. Contacting the two starting compounds can be accomplished by mixing them. Mixture of the two compounds can be carried out, for example, by magnetic stirring. A mixture may be a solution or a suspension. Step a) preferably comprises preparing a mixture of acid and gentisic acid up to the reflux temperature of the liquid forming part of the solution or suspension, preferably until a solution is obtained. In certain embodiments, the mixture is preferably maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, even more preferably 10 hours to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid or gentis acid. . Preferably, the liquid is an alkanol, aliphatic hydrocarbon, aromatic hydrocarbon, ether, ketone, ester, dichloromethane, chloroform, dimethylsulfoxide, acetonitrile, water and mixtures thereof, preferably water, acetonitrile, methanol, isopropanol , ethyl acetate, acetone, methyl isobutyl ketone, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichloromethane, xylenes, heptanes, and mixtures thereof.

In another specific embodiment, when the co-crystal forming compound is urea, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl in step a) )cyclopentane carboxylic acid and urea in a molar ratio of 9:1 to 1:1.5, preferably 1:1 to 1:1.5, preferably 1:1 to 1:1.2. Contacting the two starting compounds can be accomplished by mixing them. Mixture of the two compounds can be carried out, for example, by magnetic stirring. A mixture may be a solution or a suspension. Step a) preferably comprises preparing a mixture of acid and area, preferably up to the reflux temperature of the liquid forming part of the solution or suspension, until a solution is obtained. In certain embodiments, the mixture is preferably maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, even more preferably 10 hours to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid or urea. Preferably, the liquid is an alkanol, aliphatic hydrocarbon, aromatic hydrocarbon, ether, ketone, ester, dichloromethane, chloroform, dimethylsulfoxide, acetonitrile, water and mixtures thereof, preferably acetonitrile, methanol, isopropanol, iso butyl acetate, acetone, methyl isobutyl ketone, dichloromethane, xylene, heptane, and mixtures thereof.

In certain embodiments, when the co-crystal forming compound is nicotinamide, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) in step a) Cyclopentane carboxylic acid and nicotinamide are in a molar ratio of 0:9 to 1:1.5, preferably 1:1 to 1:1.5, preferably 1:1 to 1:1.2. Contacting the two starting compounds can be accomplished by mixing them. Mixture of the two compounds can be carried out, for example, by magnetic stirring. A mixture may be a solution or a suspension. Preferably step a) comprises preparing a mixture of acid and nicotinamide, preferably up to the reflux temperature of the liquid forming part of the solution or suspension until a solution is obtained. In certain embodiments, the mixture is preferably maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, even more preferably 10 hours to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid or nicotinamide. . Preferably, the liquid is an alkanol, aliphatic hydrocarbon, aromatic hydrocarbon, ether, ketone, ester, dichloromethane, chloroform, dimethylsulfoxide, acetonitrile, water and mixtures thereof, preferably acetonitrile, acetone, methyl isobutyl It is selected from the group consisting of ketones and mixtures thereof.

As used herein, the term alkyl includes straight or branched hydrocarbon chains having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and no unsaturation. When the term alkyl is accompanied by an expression indicating the number of carbon atoms, such as C ₁ -C ₃ , it is meant that the alkyl has the specified number of carbon atoms, such as 1 to 3 carbon atoms.

As used herein, the term alkanol includes straight or branched alkyl chains as previously defined linked to hydroxyl groups (OH). Preferred alkanols are isopropanol, propanol, ethanol, methanol, butanol, tert-butanol, isobutanol and mixtures thereof, more preferably isopropanol, propanol, ethanol, methanol and mixtures thereof.

As used herein, the term aliphatic hydrocarbon is saturated or has one or more unsaturations (double or triple bonds), eg 1, 2 or 3 unsaturations, linear, branched or cyclic; It refers to a compound composed of carbon and hydrogen atoms, preferably having 5 to 12 carbon atoms, more preferably 5 to 8 carbon atoms, and still more preferably 6 or 7 carbon atoms. Examples of aliphatic hydrocarbons are pentane, hexane, heptane, cyclopentane, cyclohexane, and mixtures thereof, among others, preferably heptane and cyclohexane and mixtures thereof.

As used herein, the term aromatic hydrocarbon consists of carbon and hydrogen atoms, is unsaturated, and is optionally selected by 1, 2 or 3 C ₁ -C ₃ alkyl groups, which may be identical or different, preferably according to Hückel's rule. Refers to a cyclic compound having 6 carbon atoms in the ring substituted with . Examples of aromatic hydrocarbons are toluene and xylene and mixtures thereof.

As used herein, the term ether refers to a compound of the formula RO-R', wherein R and R' are (a) selected from alkyl chains as previously defined, (b) wherein R and R' together form an alkylene chain -(CH ₂ ) _m (m is an integer selected from 4 to 6) optionally substituted with a C ₁ -C ₃ alkyl group, or (c) wherein R and R' together are -(CH ₂ ) form an _n -O-(CH ₂ ) _p - group (n and p integers are independently selected from 1 to 3); Examples of ethers are in particular diethyl ether, tert-butylmethyl ether, dioxane, tetrahydrofuran, methyltetrahydrofuran and mixtures thereof.

As used herein, the term ketone refers to a compound of the formula R-C(=0)-R', wherein R and R' are independently selected from alkyl radicals as previously defined. Examples of ketones are in particular acetone and methylisobutylketone and mixtures thereof.

As used herein, the term ester refers to the group R-COOR', wherein R and R' are independently alkyl radicals as previously defined. Examples of esters are ethyl acetate and isobutyl acetate and mixtures thereof.

As used herein, the term gentisic acid is used in this document to designate the compound having the IUPAC name 2,5-dihydroxybenzoic acid.

As used herein, the term urea is used herein to designate compounds having the formula (NH ₂ ) ₂ -C=O.

As used herein, the term nicotinamide is used in this document to designate a compound having the IUPAC name 3-pyridinecarboxamide.

According to one embodiment of the present invention, the liquid of step a) is water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, i-butyl acetate, propan-2-one (acetone), methyl-iso Butyl-ketone (MIBK), tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), p-xylene, diethyl ether, methyl tert-butyl ether (TMBE) and heptane, and their It is selected from the group consisting of mixtures.

The volume of liquid used in the process can be determined by one skilled in the art. Preferably, the volume (ml) of 1 to 50 times the molar amount of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid is used, more preferably 1 to 10 times.

A person skilled in the art knows that (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl) cyclopentane carboxylic acid co-crystals can be determined by, for example, thin layer chromatography, nuclear magnetic resonance Alternatively, it can be determined through routine procedures when formed using high-performance liquid chromatography.

Once the co-crystal is formed, step b) is carried out, ie the resulting co-crystal is isolated by conventional processes in the field, for example filtration.

Preferably, step b) may further comprise washing the resulting co-crystal to remove impurities and drying the co-crystal. Washing is preferably carried out with the same liquid as used in step a). Drying is preferably carried out in vacuum and at room temperature.

Combinations and Pharmaceutical Compositions

The invention also provides a combination product comprising a co-crystal of the invention and one or more therapeutic agents selected from: a) angiotensin converting enzyme inhibitors (ACE-inhibitors), b) angiotensin receptor antagonists, c) statins, d) beta blockers, e) calcium antagonists and f) diuretics.

Examples of ACE-inhibitors are, for example, captopril, enalapril, and benazepril, among others.

Examples of angiotensin receptor antagonists are in particular losartan, azilsartan, irbesartan and eprosartan.

Examples of statins are in particular atorvastatin, fluvastatin, simvastatin and lovastatin.

Examples of beta-blockers are, for example, acebutol, atenolol, betaxolol, carvedilol and propanolol, among others.

Examples of calcium antagonists are in particular amlodipine, verapamil, vidipine and isradipine.

Examples of diuretics are in particular chlorothiazide, chlorthalidone, furosemide and spironolactone.

The combination product may be a pharmaceutical composition comprising a co-crystal and one or more therapeutic agents. Alternatively, the co-crystal and one or more therapeutic agents in the combination product differ in composition.

Moreover, the present invention also encompasses a pharmaceutical composition comprising a co-crystal as defined above or a combination as defined above and a pharmaceutically acceptable excipient. In particular, the co-crystal is a therapeutically effective amount. When present, the therapeutic agent is also preferably in a therapeutically effective amount.

An “effective amount” or “therapeutically effective amount” of a drug or pharmacologically active agent means an amount of the drug or agent that is non-toxic but sufficient to provide the desired effect. An “effective” amount will vary from subject to subject, depending on the subject's age and general condition, the particular active agent or agent, and the like. Therefore, it is not always possible to specify an exact “effective amount”. However, an "effective" amount appropriate in an individual case can be determined by one skilled in the art using routine experimentation.

The co-crystal of the present invention and one or more therapeutic agents as defined above may be administered simultaneously, sequentially or separately.

Concomitant administration may occur, for example, in the form of a composition comprising a co-crystal of the present invention and one or more therapeutic agents as defined above, or formulated independently, i.e. not part of the same composition, and a co-crystal of the present invention and the above concomitant administration of one or more therapeutic agents as defined herein, i.e. simultaneous administration.

Sequential administration preferably means administration of a co-crystal of the present invention at one time point and one or more therapeutic agents as defined above in a staggered manner at different time points.

Separate administration preferably means administration of the co-crystal of the present invention and one or more therapeutic agents as defined above at different time points independently of each other.

The term "pharmaceutically acceptable excipient" refers to a carrier, diluent or adjuvant with which the active ingredient is administered. Such pharmaceutical excipients may be sterile liquids such as water and oils including petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil and the like. Especially for injectable solutions, water or aqueous co-crystal solutions and aqueous solutions of dextrose and glycerol are preferably used as carriers.

Examples of pharmaceutically acceptable excipients for orally administered pharmaceutical compositions of the present invention include conventional excipients known in the art such as binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrroly. money; fillers such as lactose, mannitol, xylitol, sorbitol, sucrose, corn starch, calcium phosphate, sorbitol, glycine, dextrose, maltodextrin, dextran, dextrin, modified starch; glidants and tablet lubricants such as magnesium stearate, calcium stearate, stearic acid, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, colloidal silicon dioxide, silicon dioxide, anhydrous colloidal silicone, glycerin, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate or talc; disintegrants such as starch, polyvinylpyrrolidone, starch sodium glycolate, crospovidone, microcrystalline cellulose, hydroxypropyl cellulose or sorbitan fatty acid esters; pharmaceutically acceptable humectants such as sodium lauryl sulfate; water solubilizing aids such as urea, betaine monohydrate, potassium sulfate, potassium acetate, mannitol; alkalizing agents such as potassium carbonate, sodium carbonate, sodium bicarbonate, trisodium phosphate, tripotassium phosphate, trisodium citrate, tripotassium citrate; sweeteners such as sodium saccharin, sodium cyclamate and aspartame; flavoring agents such as menthol and peppermint oil.

The pharmaceutical composition of the present invention may be administered parenterally, orally or topically, preferably by the oral route.

In a preferred embodiment, the pharmaceutical composition is in dosage forms suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable dosage unit form. Suitable excipients such as fillers, buffers or surfactants may be used.

The pharmaceutical composition may also be in solid or liquid oral form. Dosage forms suitable for oral administration may be tablets, capsules, syrups, solutions or powder solutions for oral suspension, granules, sachets. Preferably the dosage form is selected from the group consisting of tablets and capsules.

The formulations will be prepared using standard methods such as those described or considered in the Spanish and US Pharmacopoeia and similar references.

medical use

The co-crystals of the present invention exhibit/retain potent antagonist activity on the A ₁ adenosine receptor.

Accordingly, the present invention also relates to a co-crystal as described above, a product of a combination of a co-crystal of the present invention with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above, for use as a medicament. It's about use.

This embodiment also includes a co-crystal of the present invention as described above, a product of a combination of a co-crystal of the present invention with one or more therapeutic agents as defined above, or formulated as a pharmaceutical composition as defined above to administer a medicament. can be manufactured

Another aspect of the invention is a co-crystal of the invention as described above, a co-crystal of the invention and as defined above for use in the treatment and/or prevention of diseases known to be ameliorated by A ₁ adenosine receptor antagonism. A combination product with one or more therapeutic agents as defined above or a pharmaceutical composition as defined above.

This embodiment also relates to a co-crystal of the present invention as described above, a co-crystal of the present invention as defined above, in the manufacture of a medicament for the treatment and/or prevention of diseases known to be ameliorated by A ₁ adenosine receptor antagonism. It may be formulated as a product of combination with one or more therapeutic agents as described above or for use as a pharmaceutical composition as previously defined.

This aspect may also be formulated as a method for treating and/or preventing a disease known to be ameliorated by adenosine A ₁ receptor antagonism, the method comprising administering to a subject in need thereof a co-crystal of the present invention as described above; and administering the product of a combination of a co-crystal of the present invention with one or more therapeutic agents as defined above or a pharmaceutical composition as defined above.

Diseases or conditions suitable for improvement by adenosine A ₁ receptor antagonism include hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure or fluid retention, myocardial reperfusion injury, asthma, hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, allergic reactions including but not limited to asthma, rhinitis and urticaria, scleroderma and any other disease caused by autoimmune diseases such as multiple sclerosis. In a preferred embodiment, the disease or condition amenable to amelioration by A1 adenosine receptor antagonism is selected from the group consisting of heart failure, acute renal failure, asthma, arterial hypertension and intradialysis hypotension.

As used herein, the terms “treat” and “treatment” refer to the reversal, alleviation, or inhibition of the progression of a disease or condition to which the term or one or more symptoms of the disease or condition applies.

As used herein, the terms "prevent" and "prevention" mean to inhibit the development of the disease or condition to which the term applies or one or more symptoms of such disease or condition.

In use according to the present invention, the co-crystal, combination product or pharmaceutical composition of the present invention may be administered 1, 2, 3, 4 or 5 times per day. In use, the co-crystal, combination product or pharmaceutical composition of the present invention can be administered until symptoms of the disease or condition being treated are reversed, alleviated or inhibited in progression.

The following non-limiting examples are intended to demonstrate the invention and should not be considered as limiting the scope of the invention.

Example

general theory

¹ H-NMR analysis. Nuclear magnetic resonance analysis was recorded on DMSO-d ₆ on a Varian Mercury 400 MHz spectrometer equipped with a 5 mm broadband probe ATB 1H/19F/X. Spectra were acquired by dissolving 5 to 10 mg of the sample in 0.7 mL of deuterated solvent.

XRPD analysis. Diffraction measurements of starting materials and screening samples were performed at ambient conditions on a PANalytical X'Pert PRO θ-θ diffractometer with a radius of 240 mm in reflection geometry, operated at 45 kV and 40 mA, equipped with Cu Kα radiation and a PIXcel detector. It became. Each sample was mounted in a silicon holder with no background and allowed to rotate at 0.25 rev/s during data collection. The measurement angle range was 3.0 to 40.0° (2θ) with a step size of 0.013°. The scanning speed was 0.082°/s (40.80 sec/step) for the starting material and 0.328°/s (10.20 sec/step) for the sample produced during the study.

로 가열하였다.DSC analysis was recorded with a Mettler Toledo DSC2. The sample was weighed into a 40 μl aluminum crucible with a pinhole lid and incubated at 25° C. at 300° C. at a rate of 10° C. min under nitrogen (50 ml/min).

heated with

Crystal stability studies were performed under accelerated stability conditions (40 °C, 75 ± 5 RH %) for one week. Samples of each type stored in XRPD silicon holders were exposed to a climate chamber. It is worth noting that these conditions are very drastic, as elevated surfaces exposed to storage conditions may favor possible crystal conversion. Samples were periodically analyzed by XRPD to observe possible deformations.

Further crystal stability studies were performed under accelerated stability conditions (40 °C, 75 ± 5 RH %). Co-crystal samples were stored in open vials and exposed to a climate chamber while maintaining precisely set conditions (40°C - 75% RH ± 5 RH). These samples were analyzed weekly for one month.

Hygroscopicity study. The hygroscopicity of the co-crystals was determined by DVS (dynamic vapor sorption) using a Q5000 TA instrument. This is a gravimetric technique that measures the amount of water absorbed or desorbed by a sample at different relative humidity (RH). At each RH level, the sample mass must reach or be allowed to reach gravimetric equilibrium (exceed the time limit) before proceeding to the next humidity level. Adsorption and desorption isotherms were performed at 25 °C in the range of 0 to 95 %RH. Samples were not pre-dried but exposed to 0% RH until a stable weight was reached prior to starting the DVS cycle. This equilibration step can remove moisture that can be adsorbed from the atmosphere. Relative humidity (RH) was controlled by a mixture of wet and dry nitrogen streams. RH was kept constant before changing to the next level until equilibrium was reached (constant weight) or until the maximum time was reached.

Example One. ( 1R,3S )-3-(5- Cyano -4-phenyl-1,3-thiazole-2- Il carbamoyl ) cyclopentane Synthesis of Carboxylic Acids

The synthesis of the compound (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid is described in patent application WO 2009/044250, incorporated herein by reference. It is described in detail in A1.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.88 (m, 4H), 1.99 (m, 1H), 2.22 (m, 1H), 2.79 (m, 1H), 3.06 (m, 1H) , 7.57 (m, 3H), 7.99 (m, 2H), 12.37 (s, 1H), 12.89 (s, 1H).

1 demonstrates the ¹ H NMR spectrum of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid.

2 demonstrates the XRPD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid.

3 is (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl showing an endothermic event starting at 179.59° C., which corresponds to the melting point of this compound. ) Demonstrate the DSC pattern of cyclopentane carboxylic acid.

Example 2. ( 1R,3S )-3-(5- Cyano -4-phenyl-1,3-thiazole-2- Il carbamoyl ) cyclopentane Preparation of co-crystals of carboxylic acids and gentis acids

Equipped with a magnetic stirrer, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid (300 mg, 0.88 mmol) and gentisic acid (169 mg, 1.10 mmol, 1.25 eq.), TBME (3 ml) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sinter funnel (porosity n° 3) and washed with TBME (2 x 0.2 mL). After drying under vacuum at room temperature, a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid was obtained. Obtained as a white solid.

4 is a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and gentisic acid from Example ² ; The H-NMR pattern spectrum is verified, confirming the 1:1 molar ratio.

The co-crystal of Example 2 was also characterized by XRPD. Figure 5 shows the corresponding pattern and Table 2 shows the main peaks.

에서 시작되는 흡열 이벤트를 나타낸다.6 demonstrates the DSC pattern of the co-crystal of Example 2, which corresponds to the melting point of the co-crystal at 181.69

represents an endothermic event starting at

Example 3. ( 1R,3S )-3-(5- Cyano -4-phenyl-1,3-thiazole-2- Il carbamoyl ) cyclopentane Preparation of co-crystals of carboxylic acid and urea

Equipped with a magnetic stirrer and (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid (260 mg, 0.77 mmol, 1.3 eq.) and urea (35.2 mg, 0.59 mmol), ACN (2 mL) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sinter funnel (porosity n° 3) and washed with ACN (2 x 0.2 mL). After drying under vacuum at room temperature, a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea was obtained as a white solid. got as

7 is a ₁ H-NMR pattern spectrum of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and urea. substantiated, which confirms a 1:1 molar ratio.

The co-crystal of Example 3 was also characterized by XRPD. Figure 8 shows the corresponding pattern and Table 3 shows the main peaks.

에서 시작되는 흡열 이벤트를 나타낸다.Figure 9 demonstrates the DSC pattern of the co-crystal of Example 3, which corresponds to the melting point of this co-crystal at 197.72

represents an endothermic event starting at

Example 4. ( 1R,3S )-3-(5- Cyano -4-phenyl-1,3-thiazole-2- Il carbamoil ) cyclopentane Preparation of co-crystals of carboxylic acid and nicotinamide

Equipped with a magnetic stirrer and (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid (400 mg, 1.17 mmol, 2 eq.) and nicotinamide (71.5 mg, 0.59 mmol), MIBK (4 mL) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sinter funnel (porosity n° 3) and washed with MIBK (3 x 0.2 mL). After drying under vacuum at room temperature, co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide were obtained as white obtained as a solid.

10 is a ¹ H-NMR pattern spectrum of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid and nicotinamide. , which confirms the 1:1 molar ratio.

The co-crystal of Example 4 was also characterized by XRPD. Figure 11 shows the corresponding pattern and Table 4 shows the main peaks.

에서 시작되는 흡열 이벤트를 나타낸다.12 demonstrates the DSC pattern of the co-crystal of Example 4, which corresponds to the melting point of this co-crystal at 189.55

represents an endothermic event starting at

Example 5. stability assay

The stability of the co-crystal form of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid was evaluated under accelerated storage conditions (40 °C, 75 ± 10 °C). 5 RH %) for 1 to 4 weeks. See the results in Table 5.

After time exposure, the co-crystal remained stable according to XRPD analysis. No amorphization or appearance of crystalline form was detected at the detection limit of the assay conditions.

Example 6. hygroscopicity study

The table below (Table 6) shows the moisture content of the parent carboxylic acid and co-crystal in the hygroscopicity study.

As can be seen from the table above, the co-crystal with gentisic acid and the co-crystal with urea are less hygroscopic than the free acid, especially at up to 75% RH. See Figures 13 to 16.

Example 7. Oral bioavailability assay

The purpose of this study was to evaluate (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-yl after a single intravenous (IV) and oral (PO) administration in male SD rats. carbamoyl) to investigate the plasma pharmacokinetics of different co-crystals obtained from cyclopentane carboxylic acid.

Animals were divided into two groups: group 1 (IV: 1 mg/kg) and group 2 (PO: 5 mg/kg). Different co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid dissolved in normal saline were administered to animals in groups 1 and 2. of the solution was administered. Blood samples predose, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (IV) and predose, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours (PO) anticoagulant were collected from sets of three rats at each time point in labeled microcentrifuge tubes containing K ₂ EDTA solution as . Plasma samples were isolated by centrifugation of whole blood and stored below -70 ± 10 °C until bioassay. All samples were processed for analysis by protein precipitation with acetonitrile and analyzed with a purpose-built LC-MS/MS method (LLOQ = 1.00 ng/ml). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool of Phoenix WinNonlin ^® (Version 6.3).

The main pharmacokinetic parameters obtained in Examples 1 to 4 are shown in Table 7 below.

C _max refers to the maximum plasma drug concentration obtained after oral administration of the drug between the time of administration and the last observation.

AUC _last refers to the area under the curve from the time of administration greater than the limit of quantification to the time of the last observation.

Clearance refers to a measure of the body's ability to remove a drug from plasma and is calculated from intravenous administration.

F% refers to bioavailability. The systemic availability of a compound after oral administration is calculated using the equation:

F (%) = (AUC _last PO x Volume IV / AUC _last IV x Volume PO) x 100

As can be seen from the table above, the co-crystal with gentisic acid, urea and nicotinamide provides higher bioavailability compared to the free acid.

Example 8. Comparative bioavailability analysis in healthy volunteers

Healthy volunteers in this study will be males 18 years of age or older to evaluate the comparative bioavailability of the compound of Example 2 versus the compound of Example 1 under fasting conditions and to investigate the effect of a high-fat, high-calorie meal. The compound will be administered orally as a single dose of Example 1 (5 mg) and Example 2 (7.3 mg). This study will have a randomized, open-ended, quadruple crossover design.

To determine comparative bioavailability, AUC _{0 -t} (AUC _{0 -t} : area under the plasma concentration-time curve from time 0 h to the last measurable concentration) and C _max (C _max : maximum observed plasma concentration (peak exposure) )) will be determined after each administration.

result

16 volunteers were included in the study. In all volunteers, the baseline sample did not show the presence of the compound of Example 1. Therefore, all data were included in all pharmacokinetic measurements and calculations without any adjustments. See Table 8.

AUC _{0 -t} = area under the curve of plasma concentration versus time to the last quantifiable sample (time t) calculated using the trapezoidal method.

AUC _{0 -∞} : Area under the curve for time extrapolated to infinity, calculated as:

AUC _{0 -∞} = AUC _{0 -t} + C _t /ke,

where C _t is the quantified concentration at time t and ke is the elimination constant. The latter will be calculated using linear regression analysis during the last monologarithmic phase of elimination (Phoenix WinNonLin). In all cases, at least three plasma concentration values are used to define the stage.

C _max : maximum concentration.

t _max = time to reach C _max .

The bioavailability of Example 1 was similar to Example 2, and the 90% confidence interval was the _{acceptance limit} for _{bioequivalence ( 80.00} % to 125.00%). The C _max of Example 2 was slightly higher when administered after a high fat meal.

Claims (23)

A co-crystal comprising:
a) (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid, and
b) a co-crystal forming compound selected from the group consisting of gentisic acid, urea and nicotinamide. According to claim 1,
The co-crystal forming compound is gentisic acid. According to claim 2,
The molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to gentisic acid in the co-crystal is from 0.9:1 to 0.9:1. 1.1:1, preferably 1:1 co-crystal. According to claim 2 or 3,
A co-crystal having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 181.69 °C. According to any one of claims 2 to 4,
6.99, 13.29, 13.42, 14.02, 17.82 ± 0.20 ± 0.20 2θ °, exhibits an X-ray powder diffraction pattern comprising 2θ ° peaks, wherein the X-ray diffraction is measured using CuKα radiation. According to claim 1,
The co-crystal forming compound is urea, a co-crystal. According to claim 6,
The molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to urea in the co-crystal is from 0.9:1 to 1.1: 1, preferably 1:1 co-crystal. According to claim 6 or 7,
A co-crystal having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 197.7°C. According to any one of claims 6 to 8,
8.32, 8.82, 13.86, 15.60, 16.47, 24.86 ± 0.20 ± 0.20 2θ ° to 2θ ° peaks, wherein the X-ray diffraction is measured using CuKα radiation. According to claim 1,
The co-crystal forming compound is nicotinamide. According to claim 10,
The molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid to nicotinamide in the co-crystal is from 0.9:1 to 1.1 :1, preferably 1:1 co-crystal. According to claim 10 or 11,
A co-crystal having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 189.55 °C. According to any one of claims 10 to 12,
6.40, 8.54, 11.75, 17.29, 20.88, 23.66 ± 0.20 ± 0.20 2θ ° to an X-ray powder diffraction pattern comprising 2θ ° peaks, wherein the X-ray diffraction is measured using CuKα radiation. A method for producing the co-crystal according to any one of claims 1 to 13,
a) (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentane carboxylic acid; and a co-crystal forming compound selected from the group consisting of gentisic acid, urea and nicotinamide in the presence of a liquid; and
b) isolating the co-crystal
Including, a method for producing a co-crystal. According to claim 14,
Liquids are water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, i-butyl acetate, propan-2-one (acetone), methyl-isobutyl-ketone (MIBK), tetrahydrofuran (THF) , 1,4-dioxane, dichloromethane (DCM), p-xylene, diethyl ether, methyl tert-butyl ether (TMBE) and heptane, and mixtures thereof. The co-crystal according to any one of claims 1 to 13, and
One or more therapeutic agents selected from the group consisting of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, statins, beta-blockers, calcium antagonists and diuretics.
A combination product comprising The co-crystal according to any one of claims 1 to 13 or the combination product according to claim 16, and
Pharmaceutically acceptable excipients
A pharmaceutical composition comprising a. The co-crystal according to any one of claims 1 to 13, the combination product according to claim 16 or the product according to claim 17 for use in the treatment or prevention of diseases known to be ameliorated by A ₁ adenosine receptor antagonism. Pharmaceutical composition according to. According to claim 18,
Diseases known to be ameliorated by A ₁ adenosine receptor antagonism consist of hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases. A co-crystal, combination product or pharmaceutical composition selected from the group. The co-crystal according to any one of claims ₁ to 13, the combination product according to claim 16, or the product according to claim 17, in the preparation of a medicament for the treatment or prevention of a disease known to be ameliorated by A1 adenosine receptor antagonism. Use of the pharmaceutical composition according to claim . According to claim 20,
Diseases known to be ameliorated by A ₁ adenosine receptor antagonism consist of hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases. A use selected from the group. A ₁ adenosine receptor antagonism by administering the co-crystal according to any one of claims 1 to 13, the combination product according to claim 16, or the pharmaceutical composition according to claim 17 to a patient in need of treatment. A method for treating a disease known to improve. According to claim 22,
Diseases known to be ameliorated by A ₁ adenosine receptor antagonism consist of hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases. A method selected from the group.

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